Background:: Cardiovascular operations are associated with an inherent bleeding tendency that sometimes leads to severe bleeding and transfusion requirement. Pharmacological intervention to minimize post-bypass bleeding and blood product transfusions has received increasing attention from both medical and economic viewpoints. Methods:: This double-blind, randomized, placebo-controlled clinical trial recruited three groups of patients (each group consisting of 50 patients) undergoing on-pump coronary artery bypass graft surgery (CABG) and blindly randomized them to receive either low aprotinin, tranexamic acid, or placebo. The results were, subsequently, evaluated and compared between the groups. All the patients were operated on by one surgeon and the same surgery team. Results:: The following variables were similar between the groups, and there was no statistically significant difference between the groups in terms of these variables: age (p value = 0.308), sex (p value = 0.973), hyperlipidemia (p value = 0.720), hypertension (p value = 0.786), smoking (p value = 0.72), and diabetes (p value = 0.960). The amounts of drainage from chest tubes were less in the aprotinin and tranexamic acid groups than the amount in the placebo group; the difference was statistically important (p value < 0.001). There was no statistically significant difference with respect to need for reoperation for bleeding between the three groups (p value = 0.998). Complications following surgery in the three groups were statistically the same and not significantly different. All the complications (myocardial infarction, pericardial effusion, neurological complication and renal complication) had a good course, and all the patients were discharged from the hospital uneventfully. There was no mortality in any group. Conclusion:: Low-dose aprotinin and tranexamic acid can significantly reduce blood loss and transfusion requirement in CABG without importantly increasing mortality and morbidity.